Exploring the experiences of junior doctors who were shielding during the COVID-19 pandemic: a qualitative study of semi-structured interviews.

BACKGROUND: The term "Shielding" was introduced in the UK during the COVID-19 pandemic to protect approximately 4 million people at highest risk from infection. Shielding was characterised by extreme isolation and applied to those with certain illnesses, disabilities, and during pregnancy. For the estimated 1300 high-risk doctors, shielding meant abrupt departure from the clinical environment. We aimed to understand the impact of shielding on junior doctors (JDs) by interviewing them and their consultants. METHODS: This qualitative study used individual semi-structured interviews and reflexive thematic analysis. Virtual interviews were conducted between Sept 2, and Nov 30, 2022, using an interview guide, including open questions around impacts on training, career, and health. 11 JDs and 2 consultants were recruited via Scotland-wide purposive and snowball sampling. Written informed consent was obtained. 12 of 13 participants were women. Eight JDs were shielding because of health issues, and three because of pregnancy. Participant specialties included primary care, secondary care, and foundation and specialty training. Interview transcripts were coded by the lead author and the second author acted as a critical friend. FINDINGS: Despite making important contributions working from home, most JDs (73%, eight of 11) felt that their work was undervalued during shielding. They felt forgotten, feeling they had to "pester" supervisors to be allocated work. All participants reported inadequate support at Occupational Health and workplace levels, including limited supervision or information about training impacts. Negative attitudes towards JDs were experienced by 82% (nine of 11) of JDs, including being denied reasonable adjustments and threatened with dismissal if not following shielding advice. Consultants described supervisory challenges including not receiving guidance or resources and ongoing issues supporting disabled and pregnant JDs beyond the pandemic. INTERPRETATION: These findings offer novel qualitative insight into the impacts of shielding on JDs in Scotland. Findings indicated that support infrastructure was not fit for purpose. Given the significant number of JDs that take prolonged leave from the clinical environment, and the JDs working with disabilities and during pregnancy, these findings are of ongoing concern. Although the sample size was small and the study was set in a specific region, these findings suggest there is potential to improve support infrastructure and move towards a more inclusive clinical environment that recognises, celebrates, and benefits from the value of a diverse workforce. FUNDING: Scottish Medical Education Research Consortium.

Ethical and practical considerations of pediatric refusal in clinical anesthesia: An educational review.

Children commonly refuse induction of anesthesia. Anesthesia providers must then decide whether to honor the child's dissent or to proceed over objection. In some circumstances, a forced induction involves restraining the child, incurring both practical and ethical harms to the patient-provider encounter. This educational review explores the practical dilemma encountered when a child dissents to induction of anesthesia. In the course of exploring this dilemma, dissent and associated terms are defined and compared, and the prominent ethical underpinnings regarding pediatric decision-making are described to clarify dissent as an ethical and practical concept. Important legal and professional standards are summarized, and practice trends are discussed to depict the current state of practice, including novel approaches to honoring pediatric dissent for elective surgeries. This information is then used to invite providers to consider where they ethically situate themselves within a legally and professionally defined space of acceptable practice. Finally, these considerations are synthesized to discuss important nuances regarding pediatric refusal, and some key questions are presented for clinicians to ponder as they consider their practice of choosing whether to honor pediatric dissent at induction.

Pharmacology of boosted and unboosted integrase strand transfer inhibitors for two-dose event-driven HIV prevention regimens among men.

BACKGROUND: Event-driven HIV prevention strategies are a priority for users who do not require daily pre-exposure prophylaxis (PrEP). Regimens containing integrase strand transfer inhibitors (INSTIs) are under evaluation as alternatives to daily PrEP. To better understand INSTI distribution and inform dosing selection we compared the pharmacology of two-dose boosted elvitegravir and unboosted bictegravir regimens in MSM. MATERIALS AND METHODS: Blood, rectal and penile secretions and rectal biopsies were collected from 63 HIV-negative MSM aged 18-49 years. Specimens were collected up to 96 h after two oral doses of tenofovir alafenamide and emtricitabine with elvitegravir boosted by cobicistat or unboosted bictegravir given 24 h apart. Antiretroviral drugs were measured by LC-MS. RESULTS: Mean bictegravir plasma concentrations remained above the 95% protein-adjusted effective concentration 96 h after dosing [273 (95% CI: 164-456) ng/mL] whereas elvitegravir plasma concentrations became undetectable 48 h after the second dose. Bictegravir and elvitegravir reached rectal tissues within 2 h after the first dose, and elvitegravir tissue concentrations [1.07 (0.38-13.51) ng/mg] were greater than bictegravir concentrations [0.27 (0.15-0.70) ng/mg]. Both INSTIs became undetectable in tissues within 96 h. Elvitegravir and bictegravir were not consistently detected in penile secretions. CONCLUSIONS: Whereas bictegravir plasma concentrations persist at least 4 days after a two-oral-dose HIV prophylaxis regimen, elvitegravir accumulates in mucosal tissues. Differing elvitegravir and bictegravir distribution may result in variable mucosal and systemic antiviral activity and can inform dosing strategies for event-driven HIV prevention.

Staged treatment of placenta accreta spectrum: A combined surgical and radiological approach.

BACKGROUND: Placenta accreta spectrum (PAS) is a rare but serious complication of pregnancy. AIMS: The aim of this study was to determine maternal and neonatal outcomes following a combined surgical and interventional radiology (IR) approach to managing PAS, and the risks associated with this technique. METHODS AND MATERIALS: Retrospective cohort study of all cases of PAS in a tertiary maternity centre between January 2001 and July 2020. Women who underwent caesarean hysterectomy for histologically confirmed PAS with a staged surgical and IR approach were compared with those who underwent caesarean hysterectomy without IR. Maternal, neonatal outcomes, surgical and radiological complications were assessed. RESULTS: Forty-six women were included in the study, and 30/46 (65.2%) underwent the staged surgical and IR approach. Women in the staged group had less overall blood loss (1794 mL vs 3713 mL; P < 0.001), less requirement for blood transfusion (40% vs 75%; P < 0.001), and a lower mean volume of packed red cells transfused (2.5 vs 6.1 units). Anaesthetic and operative times were longer for the staged group (468 vs 189 min: 272 vs 141 min P < 0.001), respectively. There were no differences in rates of neonatal or maternal complications between the two groups. CONCLUSION: This study demonstrates that a staged procedure combining surgery and IR for PAS results in a considerable reduction in blood loss, need for transfusion, and units of packed red cells transfused compared with surgery alone. The staged procedure required significantly longer anaesthetic and operative times; however, there were no differences in maternal and neonatal morbidity.

ON LIVER FLUKE (FASCIOLA HEPATICA) IN CAPTIVE VICUÑAS (VICUGNA VICUGNA) AT KNOWSLEY SAFARI, PRESCOT, UNITED KINGDOM.

Knowsley Safari (KS), Prescot, United Kingdom houses a variety of captive exotic ungulates. As part of their animal welfare plan, a prospective coprological survey was undertaken for liver fluke. In June 2021, 330 fecal samples, representative of 18 exotic ungulate species, were processed by sedimentation and filtration, with examination by coproscopy. Finding fascioliasis in all five vicuña alone, with fecal egg counts ranging from one to eight eggs per gram, anthelminthic treatment was attempted twice, with three coprological reviews. While the first anthelminthic treatment (oxyclozanide) was equivocal, the second anthelminthic treatment (triclabendazole) was proven effective upon two later follow-ups. An initial malacological survey of 16 freshwater sites in KS, first found Galba truncatula at two sites in June 2021, then upon more extensive searching subsequently within the vicuña's enclosure. It appears that F. hepatica was locally acquired, being the first report of fascioliasis within captive vicuñas in the United Kingdom. To develop a better fluke-management plan, regular coprological and malacological surveillance is justified, perhaps with molecular xenomonitoring of snails, alongside prompt administration of appropriate flukicide as required.

HIV antiretroviral therapy and prevention use in US blood donors: a new blood safety concern.

Antiretroviral therapy (ART) to treat and pre-exposure prophylaxis (PrEP) to prevent HIV infection are effective tools to help end the HIV epidemic. However, their use could affect HIV transfusion-transmission risk. Three different ART/PrEP prevalence analyses in blood donors were conducted. First, blood samples from HIV-positive and a comparison group of infection-nonreactive donors were tested under blind using liquid chromatography-tandem mass spectrometry for ART. Second, blood donor samples from infection-nonreactive, 18- to 45-year-old, male, first-time blood donors in 6 US locations were tested for emtricitabine and tenofovir. Third, in men who have sex with men (MSM) participating in the 2017 Centers for Disease Control and Prevention National HIV Behavioral Surveillance (NHBS) from 5 US cities, self-reported PrEP use proximate to donation was assessed. In blind testing, no ART was detected in 300 infection-nonreactive donor samples, but in 299 HIV confirmed-infected donor samples, 46 (15.4%; 95% confidence interval [CI], 11.5% to 20.0%) had evidence of ART. Of the 1494 samples tested from first-time male donors, 9 (0.6%; 95% CI, 0.03% to 1.1%) had tenofovir and emtricitabine. In the NHBS MSM survey, 27 of 591 respondents (4.8%; 95% CI, 3.2% to 6.9%) reported donating blood in 2016 or 2017 and PrEP use within the same time frame as blood donation. Persons who are HIV positive and taking ART and persons taking PrEP to prevent HIV infection are donating blood. Both situations could lead to increased risk of HIV transfusion transmission if blood screening assays are unable to detect HIV in donations from infected donors.

Pharmacokinetics of vaginally applied integrase inhibitors in macaques.

OBJECTIVES: We conducted a detailed pharmacokinetic assessment in macaques treated with vaginal gels formulated with HIV integrase strand transfer inhibitors (INSTIs) to better understand drug distribution and identify INSTI concentrations associated with previously demonstrated in vivo protection against vaginal simian HIV challenge. METHODS: Six macaques received vaginal gel containing 1% raltegravir (30 mg) once-weekly over 6 weeks. Following a washout period, five macaques received once-weekly gel containing 0.23% L-870,812 (7 mg). Drug concentrations were measured in plasma, mucosal fluids and vaginal tissues at baseline and 2, 5 and 24 h post-dosing. RESULTS: The median maximum concentration (Cmax) for raltegravir and L-870,812 in plasma was below the limit of quantification and 41.1 ng/mL, respectively. The Cmax in vaginal fluids (1441 and 1250 µg/mL) and tissues (266.7 and 368.4 µg/g) was achieved 2-5 h after dosing, respectively. A similar half-life was observed for raltegravir and L-870,812 in vaginal fluids (8-10 h) and remained 3-4 orders of magnitude above the protein-adjusted IC95 (0.016 and 0.106 µg/mL, respectively) at 24 h. Drug concentrations in vaginal fluids correlated well with those in vaginal tissues (Pearson r ≥ 0.788). Both drugs were consistently detected in rectal fluids 2 h after vaginal dosing, albeit at much lower levels (31-92-fold) than those in vaginal fluids. CONCLUSIONS: To the best of our knowledge, this study provides the first data on INSTI levels in vaginal tissues associated with in vivo protection and demonstrates rectal drug distribution of INSTIs after vaginal dosing. These findings may inform dose selection for topical products with INSTIs for HIV prevention.

Antiretroviral drug exposure in urethral and glans surface sampling of the penis.

BACKGROUND: HIV exposure to penile tissues provides a risk of acquisition among men, yet studies evaluating penile antiretroviral (ARV) drug distribution have been lacking. We measured ARVs on urethral and glans surface swabs collected following a dose of tenofovir alafenamide, emtricitabine, elvitegravir, darunavir and cobicistat. METHODS: Thirty-five HIV-negative male participants provided urethral swabs, glans swabs, rectal swabs, blood and urine up to 96 h following a single dose of tenofovir alafenamide/emtricitabine/elvitegravir/cobicistat and darunavir. ARVs were measured by liquid chromatography-mass spectrometry with a lower limit of detection (LOD) of 1 ng/swab for swabs and 10 ng/mL for plasma and urine. Concentrations are reported as median and range. RESULTS: Urethral swab emtricitabine and darunavir concentrations peaked at 4 h for emtricitabine (36 ng/swab; 3-307 ng/swab) and 8 h for darunavir (25 ng/swab; 2-52 ng/swab). Glans swab emtricitabine and darunavir concentrations peaked 24 h after dosing (emtricitabine 14 ng/swab,

The feasibility of modified HIV and antiretroviral drug testing using self-collected dried blood spots from men who have sex with men.

BACKGROUND: In the US, one in six men who have sex with men (MSM) with HIV are unaware of their HIV infection. In certain circumstances, access to HIV testing and viral load (VL) monitoring is challenging. The objective of this study was to evaluate the feasibility of conducting laboratory-based HIV and antiretroviral (ARV) drug testing, and VL monitoring as part of two studies on self-collected dried blood spots (DBS). METHODS: Participants were instructed to collect DBS by self-fingerstick in studies that enrolled MSM online. DBS from the first study (N = 1444) were tested with HIV serological assays approved by the Food and Drug Administration (FDA). A subset was further tested with laboratory-modified serological and VL assays, and ARV levels were measured by mass spectrometry. DBS from the second study (N = 74) were only tested to assess VL monitoring. RESULTS: In the first study, the mail back rate of self-collected DBS cards was 62.9%. Ninety percent of DBS cards were received at the laboratory within 2 weeks from the day of collection, and 98% of the cards had sufficient spots for one assay. Concordance between FDA-approved and laboratory-modified protocols was high. The samples with undetectable ARV had higher VL than samples with at least one ARV drug. In the second study, 70.3% participants returned self-collected DBS cards, and all had sufficient spots for VL assay. High VL was observed in samples from participants who reported low ARV adherence. CONCLUSIONS: In these studies, MSM were able to collect and provide adequate DBS for HIV testing. The FDA-approved and laboratory-modified testing algorithms performed similarly. DBS collected at home may be feasible for HIV testing, ARV measurement, and monitoring viral suppression.

Normally functioning quadricuspid aortic valve mistaken for bicuspid valve in a septuagenarian.

A 70-year-old male underwent transthoracic (TTE) and transesophageal (TEE) echocardiography for a stroke. A bicuspid aortic valve was suspected by TTE, but TEE revealed a normally functioning quadricuspid aortic valve. A quadricuspid aortic valve may be more common than generally thought, as it may not be readily diagnosed by TTE, and may remain functionally normal.

A Technical Assistance Curriculum for Expanding Sustainable School-Based Oral Health Programs in the Carolinas' Dental Safety Net.

PURPOSE: School-based oral health programs (SBOHPs) provide opportunities to address oral health inequities by providing convenient access points for care. No published guidelines on SBOHP implementation existed. Our work describes how philanthropic, public, and academic organizations partnered to support dental safety net providers with designing comprehensive SBOHPs in North and South Carolina. DESCRIPTION: A multi-sector leadership team was established to manage a new SBOHP philanthropic-funded grant program organized into two phases, Readiness and Implementation, with the former a 6-month planning period in preparation of the latter. Readiness included technical assistance (TA) delivered through coaching and 15 online learning modules organized in four domains: operations, finance, enabling services, and impact. Organizations could apply for implementation grants after successful TA completion. Process evaluation was used including a Readiness Stoplight Report for tracking progression. ASSESSMENT: Ten Readiness grantees completed the TA. A variety of models resulted, including mobile, portable and fixed clinics. Descriptive analysis was conducted on the readiness stoplight reports. Components of the operation and finance domains required were the most time-intensive, specifically the development of policy manuals, production goals, and financial performance tracking. CONCLUSION: The program's structure resulted in (a) a two-state learning community, (b) SBOHP practice and policy alignment, and (c) coordinated program distribution. TA improvements are planned to account for COVID-19 threats, including school closures, space limitations, and transmission fears. Telehealth, non-aerosolizing procedures, and improved scheduling and communication can address concerns. Organizations considering SBOHPs should explore similar recommendations to navigate adverse circumstances.

The role of dental insurance in mitigating mortality among working-age U.S. adults with periodontitis.

AIM: To assess the relationship of dental insurance with all-cause mortality and mortality due to cardiovascular diseases (CVD), diabetes mellitus (DM), and cerebrovascular diseases (CBD) among those with periodontitis. MATERIALS AND METHODS: NHANES III and its associated mortality data set were used in this study. The outcome variables were "all-cause mortality" and "combined mortality" due to CVD, DM, and CBD. The independent variable was dental insurance stratified over periodontitis status. Unweighted frequencies with weighted column percentages were used for descriptive statistics, and chi-square test was applied for significance. Cox proportional hazard models were used for stratified multivariable analyses. All analyses were performed in SAS v9.4 accounting for survey data complexities. Significance level was kept at 5%. RESULTS: The mortality was 14.58% for all-cause mortality and 4.06% for combined mortality among those with periodontitis in this study. Dental insurance significantly reduced the hazard of all-cause mortality among those with periodontitis (HR: 0.75; 95% CI: 0.61 - 0.93), adjusted for covariates. However, no association of dental insurance with combined mortality was observed among periodontitis group. CONCLUSIONS: Dental insurance reduces hazard of all-cause mortality among those with periodontitis. Dental insurance ensures access to dentists and improves oral and dental health. Longitudinal study is needed to establish causality.

Evaluation of Rapid Testing Algorithms for Venue-based Anonymous HIV Testing among Non-HIV-Positive Men Who Have Sex with Men, National HIV Behavioral Surveillance (NHBS), 2017.

HIV rapid testing algorithms (RTAs) using any two orthogonal rapid tests (RTs) allow for on-site confirmation of infection. RTs vary in performance characteristics therefore the selection of RTs in an algorithm may affect identification of infection, particularly if acute. National HIV Behavioral Surveillance (NHBS) assessed RTAs among men who have sex with men recruited using anonymous venue-based sampling. Different algorithms were evaluated among participants who self-reported never having received a positive HIV test result prior to the interview. NHBS project areas performed sequential or parallel RTs using whole blood. Participants with at least one reactive RT were offered anonymous linkage to care and provided a dried blood spot (DBS) for testing at CDC. Discordant results (RT-1 reactive/RT-2 non-reactive) were tested at CDC with lab protocols modified for DBS. DBS were also tested for HIV-1 RNA (VL) and antiretroviral (ARV) drug levels. Of 6500 RTAs, 238 were RT-1 reactive; of those, 97.1% (231/238) had concordant results (RT-1/RT-2 reactive) and 2.9% (7/238) had discordant results. Five DBS associated with discordant results were available for confirmation at CDC. Four had non-reactive confirmatory test results that implied RT-1 false reactivity; one had ambiguous confirmatory test results which was non-reactive in further testing. Regardless of order and type of RT used, RTAs demonstrated high concordant results in the population surveyed. Additional laboratory testing on DBS following discordant results confirmed no infection. Implementing RTAs in the context of anonymous venue-based HIV testing could be an option when laboratory follow-up is not practicable.

Efficacy of Vaginally Administered Gel Containing Emtricitabine and Tenofovir Against Repeated Rectal Simian Human Immunodeficiency Virus Exposures in Macaques.

Vaginal microbicides containing antiretrovirals (ARVs) have shown to prevent vaginally acquired human immunodeficiency virus (HIV), but these products may not protect women who engage in anal sex. Intravaginal dosing with ARVs has shown to result in drug exposures in rectal tissues, thus raising the possibility of dual compartment protection. To test this concept, we investigated whether intravaginal dosing with emtricitabine (FTC)/tenofovir (TFV) gel, which fully protected macaques against repeated vaginal exposures to simian human immunodeficiency virus (SHIV), protects against rectal SHIV exposures. Pharmacokinetic studies revealed rapid distribution of FTC and TFV to rectal tissues and luminal fluids, albeit at concentrations 1-2 log10 lower than those in the vaginal compartment. Efficacy measurements against repeated rectal SHIV challenges demonstrated a 4.5-fold reduction in risk of infection in macaques that received intravaginal FTC/TFV compared to placebo gel (P = .047; log-rank test). These data support the concept of dual compartment protection by vaginal dosing and warrants developing ARV-based vaginal products with improved bidirectional dosing.

As if the disease was not enough: coping with the financial consequences of cancer.

PURPOSE: The goal of this research was to understand how cancer survivors cope with the financial consequences of their disease. METHODS: Twenty-six cancer survivors who self-identified as having experienced financial hardship related to their disease were interviewed. Transcripts of these interviews were analyzed using constructivist grounded theory approach. An analysis of codes related to coping strategies was conducted, and findings were stratified based on established coping theories (Lazarus and Folkman and Moos and Holahan) previously applied to coping with serious/chronic illnesses. RESULTS: Participants used both person-oriented/emotion-focused and task/problem-focused coping skills to confront the financial consequences of their disease trajectory. Problem-focused skills included dealing with debt, accessing financial assistance, making lifestyle changes, seeking information and education, altering treatment protocols, being proactive, and negotiating insurance. Emotion-focused tasks included using personal strengths, expressing emotion, accessing social support, being determined, and taking care of oneself. Results were further analyzed using Moos and Holahan's framework of coping skills; examples of each of these coping skills were identified in the interview data. CONCLUSIONS: Facing serious financial ramifications due to a cancer diagnosis calls forth coping skills and tasks that can be categorized using coping theories traditionally applied to coping with the illness itself. Cancer patients are often confronted with dual threats: the physical and emotional impact of the illness and the loss of financial security and the lifestyle that they have worked to maintain. Interventions with cancer survivors should include facilitating effective coping with the financial implications of the disease.

Elevating Oral Health Interprofessional Practice Among Pediatricians Through a Statewide Quality Improvement Learning Collaborative.

CONTEXT: Because of persistent effects of early childhood caries and impacts of dental health professional shortages areas, the integration of oral health in primary care settings is a public health priority. In this study, we explored oral health interprofessional practice (OHIP) as an integrative pathway to reduce oral health disparities. OHIP can include performing oral health risk assessments, describing the importance of fluoride in the drinking water, implementing fluoride varnish application, and referring patients to a dental home. OBJECTIVE: To conduct a formative evaluation of how 15 pediatric primary care practices implemented the adoption of OHIP in their clinical settings. DESIGN: Using an ecological framework, we conducted a qualitative process evaluation to measure the factors that inhibited and facilitated OHIP adoption into pediatric settings. Document review analysis and qualitative interviews were conducted with pediatric practices to contextualize challenges and facilitators to OHIP adoption. SETTING AND PARTICIPANTS: A total of 15 Children's Health Insurance Program Reauthorization Act pediatric practices located in 13 South Carolina counties participated in this study. MAIN OUTCOME MEASURES: Outcomes of interest were the facilitators and challenges of OHIP adoption into pediatric primary care practices. RESULTS: Thematic analysis revealed challenges for OHIP adoption including limited resources and capacity, role delineation for clinical and administrative staff, communication, and family receptiveness. OHIP training for clinical practitioners and staff and responsiveness from clinical staff and local dentists were facilitators of OHIP adoption. Twelve key recommendations emerged on the basis of participant experiences within OHIP, with developing an active dental referral network and encouraging buy-in from clinical staff for OHIP adoption as primary recommendations. CONCLUSION: We demonstrated the effectiveness of a learning collaborative meeting among pediatric primary care providers to adopt OHIPs. This work reveals an actionable pathway to support oral health equity advancement for children through an additional access point of preventive oral care, reinforcement of positive oral health behaviors, and interaction between parent and child for overall health and wellness of the family.

The Female Genital Tract Microbiome Is Associated With Vaginal Antiretroviral Drug Concentrations in Human Immunodeficiency Virus-Infected Women on Antiretroviral Therapy.

Background: The female genital tract (FGT) microbiome may affect vaginal pH and other factors that influence drug movement into the vagina. We examined the relationship between the microbiome and antiretroviral concentrations in the FGT. Methods: Over one menstrual cycle, 20 human immunodeficiency virus (HIV)-infected women virologically suppressed on tenofovir (TFV) disoproxil fumarate/emtricitabine and ritonavir-boosted atazanavir (ATV) underwent serial paired cervicovaginal and plasma sampling for antiretroviral concentrations using high-performance liquid chromatography-tandem mass spectrometry. Analysis of 16S ribosomal RNA gene sequencing of cervicovaginal lavage clustered each participant visit into a unique microbiome community type (mCT). Results: Participants were predominantly African American (95%), with a median age of 38 years. Cervicovaginal lavage sequencing (n = 109) resulted in a low-diversity mCT dominated by Lactobacillus (n = 40), and intermediate-diversity (n = 28) and high-diversity (n = 41) mCTs with abundance of anaerobic taxa. In multivariable models, geometric mean FGT:plasma ratios varied significantly by mCT for all 3 drugs. For both ATV and TFV, FGT:plasma was significantly lower in participant visits with high- and low-diversity mCT groups (all P < .02). For emtricitabine, FGT:plasma was significantly lower in participant visits with low- vs intermediate-diversity mCT groups (P = .002). Conclusions: Certain FGT mCTs are associated with decreased FGT antiretroviral concentrations. These findings are relevant for optimizing antiretrovirals used for biomedical HIV prevention in women.

A Dose Ranging Pharmacokinetic Evaluation of IQP-0528 Released from Intravaginal Rings in Non-Human Primates.

PURPOSE: Design of intravaginal rings (IVRs) for delivery of antiretrovirals is often guided by in vitro release under sink conditions, based on the assumption that in vivo release will follow a similar release profile. METHODS: We conducted a dose-ranging study in the female reproductive tract of pigtail macaques using matrix IVRs containing IQP-0528, a poorly soluble but highly potent antiretroviral drug with an IC90 of 146 ng/mL. These IVRs consisted of drug-loaded segments, 15.6% IQP-0528 in Tecoflex 85A, comprising either all, half, or a quarter of the entire ring. RESULTS: In vitro release under sink conditions demonstrates loading-proportional release, with a cumulative 30-day release of 48.5 ± 2.2 mg for our 100% loaded ring, 24.8 ± .36 mg from our 50% loaded ring, and 13.99 ± 1.58 mg from our 25% loaded ring. In vivo, while drug concentration in vaginal fluid is well in excess of IQP-0528's EC90, we find no statistical difference between the different ring loadings in either swab drug levels or drug released from our rings. CONCLUSIONS: We show that in vitro release may not accurately reflect in vivo release, particularly for poorly soluble drugs. All tested loadings of our IVRs are capable of delivering IQP-0528 well in excess of the IC90.

Safety and Pharmacokinetics of Quick-Dissolving Polymeric Vaginal Films Delivering the Antiretroviral IQP-0528 for Preexposure Prophylaxis.

For human immunodeficiency virus (HIV) prevention, microbicides or drugs delivered as quick-dissolving films may be more acceptable to women than gels because of their compact size, minimal waste, lack of an applicator, and easier storage and transport. This has the potential to improve adherence to promising products for preexposure prophylaxis. Vaginal films containing IQP-0528, a nonnucleoside reverse transcriptase inhibitor, were evaluated for their pharmacokinetics in pigtailed macaques. Polymeric films (22 by 44 by 0.1 mm; providing 75% of a human dose) containing IQP-0528 (1.5%, wt/wt) with and without poly(lactic-co-glycolic acid) (PLGA) nanoparticle encapsulation were inserted vaginally into pigtailed macaques in a crossover study design (n = 6). With unencapsulated drug, the median (range) vaginal fluid concentrations of IQP-0528 were 160.97 (2.73 to 2,104), 181.79 (1.86 to 15,800), and 484.50 (8.26 to 4,045) µg/ml at 1, 4, and 24 h after film application, respectively. Median vaginal tissue IQP-0528 concentrations at 24 h were 3.10 (0.03 to 222.58) µg/g. The values were similar at locations proximal, medial, and distal to the cervix. The IQP-0528 nanoparticle-formulated films delivered IQP-0528 in vaginal tissue and secretions at levels similar to those obtained with the unencapsulated formulation. A single application of either formulation did not disturb the vaginal microflora or the pH (7.24 ± 0.84 [mean ± standard deviation]). The high mucosal IQP-0528 levels delivered by both vaginal film formulations were between 1 and 5 log higher than the in vitro 90% inhibitory concentration (IC90) of 0.146 µg/ml. The excellent coverage and high mucosal levels of IQP-0528, well above the IC90, suggest that the films may be protective and warrant further evaluation in a vaginal repeated low dose simian-human immunodeficiency virus (SHIV) transmission study in macaques and clinically in women.